Grapevine fanleaf virus (GFLV) is a causative agent of fanleaf degeneration in vineyards worldwide, leading to drastic losses in a high commodity crop. GFLV infection modulates host metabolic and immune pathways to result in leaf mottling and chlorosis, as well as uneven fruit set and ripening. Symptoms of GFLV-infected vines in diseased vineyards are defined by the ‘patchy’ radial spread in relation to the mobility of the ectoparasitic dagger nematode vector Xiphinema index. GFLV (species Nepovirus foliumflabelli, genus Nepovirus, family Secoviridae) is grouped within the order Picornavirales with cowpea mosaic virus and poliovirus. Like all members of Picornavirales, GFLV encodes a putative viral RNA-dependent RNA polymerase (protein 1EPol*/Sd) to accomplish replication of the viral genome. Previous work elucidated that the C-terminal region of protein 1EPol*/Sd is a symptom determinant, where a single amino acid is necessary but not sufficient to induce symptoms in the model plant Nicotiana benthamiana. Given the differences in reaction of this plant host to wildtype and mutant GFLV strains, I sought out to document differences in molecular host regulation to shed light on the function of the elusive symptom determinant. In Chapter 1 of this dissertation, I summarize current understandings of GFLV biology and symptom development upon infection. Despite many advances, limited information is available on the host reaction to GFLV infection. In Chapter 2, I conducted a systematic review of grapevine viruses and their study in model herbaceous plant hosts. Grapevine virology has benefitted greatly from the basic and translational research conducted in faster growing, annual plants. Herbaceous hosts have been, and will continue to be, an excellent tool to understand more about grapevine virus biology, including GFLV biology. In Chapter 3, I summarize efforts in in silico predictive protein modeling of all GFLV proteins, alongside Dr. Choi, to update the current understandings of the viral proteome repertoire and to gain further insights in potential unknown protein domains. In Chapter 4, I document the capacity of wildtype GFLV strains, as well as engineered mutants, to modulate the immune system of the model plant host Nicotiana benthamiana for sustaining infection. I profiled the abundance of transcripts and proteins to explore virus-host interactions by using 3’RNA-sequencing and tandem liquid chromatography mass spectrometry analyses (LC-MS/MS). In Chapter 5, I characterize the root system architecture (RSA) traits of N. benthamiana infected by thirteen wildtype and mutant GFLV strains, and document for the first time, GFLV induced symptomatology in root systems. I employed 3’RNA-Seq to determine differentially abundant transcripts found in root tissue of plants infected with different GFLV strains. The differentially abundant gene categories indicated disruptions to host pathways for inositol signaling, RNA silencing, and production of reactive oxygen species upon infection with symptomatic GFLV strains. In Chapter 6, I describe a unified mechanism of the host response to GFLV by integrating all the ‘omics datasets previously produced. GFLV infection induced reactive oxygen species production and modified inositol-mediated signaling in root and leaf tissue, ultimately showing parallels in the infection of root and leaf tissue. Predictive protein modeling indicated a phosphatase domain in the central region of protein 1EPol*/Sd, which was hypothesized to be involved in immune regulatory pathways. In Chapter 7, I document varying levels of transmission in relation to GFLV strains by using a one-step or continuous transmission assay. The identity of the viral strain and identity of the amino acid at position 802 of the protein 1EPol*/Sd both contributed to the transmission rate of GFLV. This work provided new molecular insights into GFLV-host-X. index interactions. Finally, the prospectives and conclusions chapter suggests future research and leading hypotheses regarding the function of GFLV protein 1EPol*/Sd. Insights on protein structure and protein localization will be imperative to confirm hypothesized functions of the C-terminal domains in protein 1EPol*/Sd. Together, my findings suggest that the C-terminal domain of protein 1EPol*/Sd is involved in the suppression of the plant host immune response, which manifests into leaf and root symptomatic phenotypes. Moreover, I uncovered differences in transmission of symptomatic and asymptomatic GFLV strains through a novel continuous transmission assay. This work has broadened our understanding of virus-host-vector interactions in a soil-borne pathogen and has uncovered molecular pathways unique to GFLV infection that are implicated in symptomatic virus-host relationships.